Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a protein secreted by many cell types which has been shown in model systems unrelated to the nervous system to perform two major functions: it is an angiogenic, endothelial-specific growth factor, and it is a potent inducer of capillary permeability. We have proposed that VEGF/VPF is also a mediator of endothelial cell proliferation and capillary permeability in the normal and diseased central nervous system. Previous results from our laboratory have demonstrated that increased VEGF/VPF expression may underlie the increased permeability associated with brain tumor vessels and the resulting edema observed in that clinical setting. Hyperpermeability associated with brain tumors and the resulting brain edema is a significant cause of morbidity and mortality in patients with brain tumors. Our continuing goals are to define the function of VEGF/VPF in the central nervous system, to understand the extent to which altered expression of VEGF/VPF contributes to the symptomatology of certain pathologic conditions, to determine the factors responsible for regulation of VEGF/VPF expression, and to develop strategies for modifying the activity of VEGF/VPF in appropriate clinical settings. The major approaches which we are using are: 1) the use of cell cultures to determine what factors regulate VEGF/VPF expression; 2) a nonreplicating effects of overexpression of VEGF/VPF in otherwise normal rodent brain; 3) two models of brain injury in rodents (stab and freeze lesion); and 4) analysis of tumor vessel permeability using quantitative autoradiography in a rodent brain tumor model to assess the efficacy and mechanism of action of clinical treatments for this disease. Our findings from this year are: 1) When injected into the normal rodent brain, an adeno-virus coding for the VEGF gene greatly increases the permeability of capillaries in the region and disrupts the blood-brain barrier. This effect is specific for VEGF/VPF, as viruses coding for other proteins do not have this effect. 2) In two models of brain injury (stab and freeze lesions), VEGF/VPF expression increased dramatically and specifically in reactive astrocytes associated with the lesions, reaching peak expression between three and seven days after injury and persisting for at least three weeks. These observations indicate that astrocytes react to injury by increasing VEGF/VPF expression, and that VEGF/VPF may be an important factor in wound healing in the CNS. 3) VEGF/VPF is up-regulated in normal astrocytes and in brain tumor cells by serum growth factors and by hypoxia. 4) he steroid dexamethasone alters VEGF/VPF activity at two levels, inhibiting both the growth factor-dependent induction of VEGF/VPF expression and the ability of VEGF/VPF to increase capillary permeability. Our experiments have shown that both of these effects occur through the glucocorticoid receptor, a finding that has important implications for the proper management of brain tumor patients.